BTF3373

PROCESS UTILITY
SYSTEMS
Dr Nadiya binti Hj Abd Halim
CHAPTER OUTLINE
01 02 03
Generation of Heating,
Types of purified water (PW) ventilation, and air
and water for conditioning
utilities
injection (WFI) (HVAC) system

04 05
Dust collection Compressed air
system generation
 01
Types of
utilities
 INTRODUCTION
Pharmaceutical utility systems
Each pharmaceutical industry’s manufacturing process uses
several support systems with different functions and is generated
and distributed with centralized installations.
These systems are not necessarily designed and customized for
users of a single production facility, but often serve an entire
factory or part of it.
PHARMACEUTICAL UTILITY SYSTEMS
The most common systems of this type are:
● Process waters ● Drinking and sanitary water
● (different types) ● Fire
● Cooling and/or heating fluids ● Fire-fighting water
● (steam, water, brain, diathermic ● Vacuum
oil, etc) • Air conditioning ● Various kinds of the waste
● (HVAC systems) system
● Compressed air, nitrogen ● (rainwater, medical, process,
● Burning gas biological, gas, etc.)
● Process gas ● Electric power
● (CO2 , O2 , etc)
PHARMACEUTICAL UTILITY SYSTEMS
Good working of these systems ensures efficiency of production.
For example, the sudden lack of steam might impair a heating
phase (e.g. during a synthesis reaction) or a sterilization cycle,
with the risk of compromising an entire batch of production. The
lack of vacuum might block a filtering or drying process, causing
damage to the product.
An accurate preventive maintenance program of the systems can
limit such incidents and subsequent blocks of production.
PHARMACEUTICAL UTILITY SYSTEMS

The production support systems used in the pharmaceutical

industry can be classified into three categories as follow:

 process systems (direct impact system)

 process support systems (indirect impact system)
 utility systems (non-impact systems)
 PROCESS SYSTEMS
(DIRECT IMPACT SYSTEMS)
They are:
• in direct contact with the product;

• in contact with those materials which will later be transformed

into the product or will be in direct contact with it.

For example, process water (water for injections, purified, or

drinking water) is generally considered a direct process system.
 PROCESS SYSTEMS
(DIRECT IMPACT SYSTEMS)

• They are always considered critical because they are actually or potentially in
direct or indirect contact with the product.
• They must be designed and constructed considering the needs of product quality and
to prevent any contamination to the product itself.
• Incorrect design and/or construction methods may leave residues on the inner
surface equipment or pipes that can cause contamination of the distributed fluid
and, consequently, of the product.
• For these reasons, it is often important to have a high degree of surface finishing,
specific methods of construction (e.g., welding), or cleaning and keeping systems
that can provide the necessary level of protection against contamination.
 PROCESS SYSTEMS
(DIRECT IMPACT SYSTEMS)
• From a GMP point of view, support systems that meet the definition of " process
systems ", should be considered real raw materials.
• Due to the fact that process systems can directly, indirectly or potentially affect
product quality, the same degree of control of the production process should be
applied to them, and they must be qualified according to the classic approach of
validation.
• It is also important to check the qualitative aspects of the material that comes to
points of use (usually consisting of a fluid), since any chemical or microbiological
contaminants or impurities would be found in final or intermediate products, and
compromise quality.
 PROCESS SUPPORT SYSTEMS
(INDIRECT IMPACT SYSTEMS)
• They directly support process operations but have no contact with the product or
with materials that will be transformed into the product.
• Some examples of support systems for the process: cooling and heating fluids that
exchange heat with process materials through a surface (heat exchange jacket
applied to reactors, tanks, dryers, etc... shell and tube, double pipe, plate
exchangers, etc…)
• The solutions used for equipment and/or machine washing (CIP systems - Cleaning
in Place or manual systems for washing) are generally considered process support
systems, except those used for the final rinsing that is considered as process
fluids.
 PROCESS SUPPORT SYSTEMS
(INDIRECT IMPACT SYSTEMS)
• The process support systems are not generally considered critical
• In these systems, in general, the qualitative aspects of the fluid have no relevance.
Instead, the physical features available at the point of use (temperature, pressure,
flow, etc..), and availability for the needs of a process in contemporary conditions
of use with other points of use have more relevance.
• From a GMP point of view, system availability to users has relevance, while the
qualification of plant and functional aspects of the system follow the Good
Engineering Practices (GEP), which are based mainly on the proper design and a
comprehensive "commissioning" of the system (drawings “as-built", tracking
changes, testing, SOPs, etc.).
 UTILITY SYSTEMS (NON-IMPACT SYSTEMS)

• They are not in contact with the product or material that will then be transformed
into the product;

• They are not customized systems to specific users but distributed with general
networks serving all the users of the factory;

• They deal with side efts of industrial production such as waste disposal.

• Examples of service systems are the systems of drinking water, sanitary water, and
electricity.
 UTILITY SYSTEMS
(NON-IMPACT SYSTEMS)
• Typically, such systems did not impact the product quality and,
therefore, are never considered critical.
• In this case also, the qualification of the plant and operating systems
follows good engineering practices (GEP).
• Electricity can instead have a critical role (e.g., Loss of data or
interruption of production processes).
• In these cases, the supply to its customer’s critical points is ensured
by appropriate systems (automatic backup generators, un-interruptible
power systems), that are able to overcome possible discontinuity of
supply from the distribution network.
 02
Generation of
purified water (PW)
and water for
injection (WFI)
 Purified water (PW) and water for
injection (WFI)
Water is widely used as raw material, inactive ingredient,
medicinal vehicle, and solvent in the processing, formulation,
and manufacture of pharmaceutical products (dosage forms),
active pharmaceutical ingredients (APIs), API intermediates,
compendial articles, and analytical reagents as well as in
cleaning applications.
 SOURCE WATER CONSIDERATIONS
• Source water is the water that enters the facility. The origin of this source of water
can be from natural surface waters like rivers and reservoirs, deep-bed well waters,
sea waters, or some combination of these
• It is the responsibility of the users of any source of water
• to ensure that the water used in the production of drug substances (API), as well as
water for indirect drug product contactor for purification system feed water purposes
meets, at a minimum, drinking (potable) water standards as defined by their the
requirements of the National Primary Drinking Water Regulations (NPDWR) (40 CFR
141) issued by the U.S. EPA or the drinking water regulations of the European Union
(EU) or Japan, or the WHO drinking water guidelines
 WATERS USED FOR PHARMACEUTICAL
MANUFACTURING AND TESTING PURPOSES

• There are many different grades of water used for pharmaceutical

purposes.

• These waters can be divided into two general types: bulk waters,
which are typically produced on-site where they are used; and
packaged waters, which are produced, packaged, and sterilized to
preserve microbial quality throughout their packaged shelf life.
Types of Water Used
 1. Non-potable water
• Non-potable water is water that is not of drinking water quality,
but which may still be used for many other purposes, depending on
its quality.
• Non-potable water is generally all raw water that is untreated,
such as that from lakes, rivers, groundwater, springs, and ground
wells.
• Purposes:
• cleaning of the outer surface of the factory
• used in the garden
• washing vehicles etc
 2. Potable water
Potable water is not suitable for general pharmaceutical use because of the
considerable amount of dissolved solids present. These dissolved solids
consist chiefly of the chlorides, sulfates, and bicarbonates of Na, K, Ca, and
Mg. A 100 ml portion of official water contains not more than 100 mg of
residue (0.1%) after evaporation to dryness on a steam bath.

Purposes:
• To use as drinking water
• Washing and the extraction of crude drugs
• Preparation of products for external use
 3. Purified water
• Purified water is used in the preparation of all medication containing
water except ampoules, injections, and some official external preparations
such as liniments.
• Purified Water must meet the requirements for ionic and organic chemical
purity and must be protected from microbial contamination
• The minimal quality source or feed water for the production of Purified
Water is Drinking Water.
 3. Purified water
Purposes:
• For the Production of non-parenteral preparation/formulation
• For the Cleaning of certain equipment used in non-parenteral product
preparation
• For Cleaning of non-parenteral product-contact components
• For All types of tests & assay
• For the Preparation of some bulk chemicals
• For the Preparation of media in microbiology labs

Preparation techniques:
• Deionization
• Distillation
• Ion Exchange
• Reverse Osmosis
• Filtration
 4. Water For Injection (WFI)

Water for Injection is a solvent used in the production of Parenteral and other
preparations where product endotoxin content must be controlled, and in
other pharmaceutical applications, Water For Injection (WFI) is sterile,
nonpyrogenic, distilled water for the preparation of products for parenteral
use. It contains no added substance and meets all the requirements of the
tests for purified water. It must meet the requirements of the pyrogen test.
The finished water must meet all of the chemical requirements for Purified
Water as well as an additional bacterial endotoxin specification.
 4. Water For Injection (WFI)
• Since endotoxins are produced by the kinds of microorganisms that
are prone to inhabit water, the equipment and procedures used by
the system to purify, store, and distribute Water for Injection must
be designed to minimize or prevent microbial contamination as well
as remove incoming endotoxins from the starting water.
• Water for Injection systems must be validated to reliably and
consistently produce and distribute this quality of water.
4. Water For Injection (WFI)
Purposes:
For the production of parenteral products/formulation
For cleaning of parenteral product-contact components

Preparation technique:
• Distillation
• Reverse osmosis
• Membrane process
 4. Water For Injection (WFI)
Storage condition:
• It can be stored for periods of up to a month in special tanks containing
ultraviolet lamps. When this freshly prepared water is stored and sterilized
in hermetically sealed containers, it will remain in good condition
indefinitely.
• If an autoclave is not available, freshly distilled water may be sterilized by
boiling the water for at least 60 minutes in a flask stoppered with a plug of
purified nonabsorbent cotton covered with gauze, tin-foil, or stout
nonabsorbent paper; or the neck of the flask may be covered with cellophane
and tightly fastened with a cord.
 5. Sterile water for injection
Its specifications are provided in the USP monograph for water for injection,
sterilized, and packaged in suitable single-dose containers, preferably of
type I glass, of not larger than 1000 ml size. It meets the requirements of
the sterility test and pyrogen test and other tests under purified water.
Purposes:
• Used for extemporaneous preparation compounding
• Used as a sterile diluent for parenteral products
Preparation technique:
• By distillation of water for injection (WFI)
 6. Bacteriostatic WFI
This is sterile Water for Injection containing bacteriostatic (antimicrobial)
agents. It may be packed in single-dose containers of not larger than 5 ml
size and in multiple-dose containers of not larger than 30 ml size, the label
of which indicates the name and the proportion of added agent.
Purposes:
• Used as a diluent in the preparation of parenteral products
Preparation technique:
• By using sterile water for injection
 7. Sterile water for Inhalation
Sterile water for Inhalation is Water for Injection that is packaged and rendered
sterile and is intended for use in inhalators and in the preparation of
inhalation solutions. It carries a less stringent specification for bacterial
endotoxins than Sterile Water for Injection, and therefore, is not suitable for
parenteral applications.
Purposes:
• Preparation of use in inhalators
• Preparation of inhalant solutions
Preparation technique:
• By sterilization of water for injection
 7. Sterile Water for Irrigation
Sterile water for irrigations is Water for Injection packages and sterilized in single-dose
containers larger than 1L in size that allows rapid delivery of its contents. It need not
meet the requirement under small-volume injections.
Purposes:
• To bath and moisten body tissue
• Performing urologic procedures for surgeon
Preparation technique:
• From water for injection
Example:
• Surgical irrigation solution (Splash solution)
• Urologic irrigation solution
• Glycine solution
• Sorbitol solution
 9. Water for hemodialysis
Water for hemodialysis is used for hemodialysis applications. It may be packaged and
stored in unreactive containers that preclude bacterial entry. The term “unreactive
containers” implies that the container, especially its water contact surfaces, are not
changed in any way by the water, such as by leaching of container-related compounds
into the water or by any chemical reaction or corrosion caused by the water. The
water contains no added antimicrobials and is not intended for injection.
Purposes:
• For the dilution of hemodialysis concentrate solution
Preparation technique:
• From safe drinking water
 10. Pure steam
Pure steam is also sometimes referred to as “clean steam”.
Purposes:
• To remove any co-deposited impurity residues
• For air humidification in controlled manufacturing environments
• Used in steam sterilization of equipment and porous loads
• For cleaning the places where condensate directly comes in contact with
official articles, product contact containers, and surfaces.
Types
of
Water
Used
DESIGN AND OPERATION OF
PURIFIED WATER AND
WATER FOR INJECTION
SYSTEMS
 DESIGN AND OPERATION OF PURIFIED
WATER AND WATER FOR INJECTION
SYSTEMS
• The design, installation, and operation of systems to produce Purified
Water And Water for Injection include similar components, control
techniques, and procedures.

• The quality attributes of the two glasses of water differ in their

bioburden expectation, the presence of abacterial endotoxin requirement
for Water for Injection, and their methods of preparation.
 Unit Operations Considerations
• To achieve the quality attributes for pharmaceutical waters, multiple-unit
operations are required.
• The design of the water purification system needs to take into
consideration different aspects, including the source water quality,
sanitization, pharmaceutical water quality attributes, uses of the water,
and maintenance programs.
• Each unit operation contributes specific purification attributes associated
with chemical and microbiological parameters
Why do we monitor these parameters?

• Conductivity: Ionic Contaminants

• TOC: Food for microbes
• Nitrates: Negative health impacts
• Heavy Metals: Toxic to humans and animals
• Aerobic Bacteria: Unwanted organisms
• Endotoxins: Dangerous in parenteral
 Generation of Purified Water

• In order to produce the chemical & microbiological quality water types

and at the same time comply with the regulations, certain instruments
are required for generating purified water.
• The raw water must be:
• Pretreated before actual purification.
• Thus, a facility for generating purified water consists of several steps,
which are described next:
 Water System
Softening Reverse Osmosis Reverse Osmosis

Purified Water
Waste Water
Waste Water

Softening Reverse Osmosis Electro

Deionization

Waste Water Waste Water

 Water for injection (WFI)
Water for injection (WFI) is required for the production
of sterile medicinal products.
The requirements of manufacturing procedures for WFI
are different in the USA, Japan and Europe (see
Figure 5.B-9).
Permissible manufacturing procedure for WFI
Europe Distillation

USP Distillation or other equivalent or superior processes

Japan Ultra filtration or distillation

Purified Water USP 23
• Purified Water is described in the USP 23 monograph as
follows:
"Purified Water is water obtained by distillation, ion-exchange
treatment, reverse osmosis, or another suitable process.

• It is prepared from water complying with the regulations of the

U.S. Environmental Protection Agency (EPA) with respect to
drinking water. It contains no added substances."
 Purified water USP
● Purified water is obtained by:
1. Distillation.
2. Ion-Exchange.
3. Reverse osmosis.
4. Other suitable method.
It is prepared from the drinking water (potable water).
It is more free of solid impurities.
When evaporated to dryness, it must not yield greater than
0.001% of residue (1mg of total solids per 100 ml of sample
evaporated).
Thus it is 100 times more free of solids than the drinking water.
 Water system design
● Pipes sloped so water does not pool and can drain easily
● Sanitary fittings & connections
● Constructed of suitable materials such as stainless steel
● Circulate the water
● Incorporate non-return valves (NRV)
 Sampling Requirements

● There must be a sampling procedure.

● S a m p le in t e g r it y m u s t b e a s s u r e d .
● S a m p le r t r a in in g
● S a m p le p o in t
● S a m p le s iz e
● S a m p le c o n t a in e r
 Softener
The potable water is first coarsely filtered, then the scale
(calcium, magnesium, sulfate, carbonate) is removed in the
first stage.
A choice procedure would be softening using ion-exchange
technology.
A sodium exchanger can be used for this purpose.
The magnesium and calcium ions present in the water are
deposited in the resin in exchange for sodium ions.
 Removal of chlorine

• Only potable water can be used to generate pharmaceutical

water.
• However, the composition can vary greatly, and it is possible
that the potable water may have been chlorinated.
• As the raw water must be free from oxidation media, de-
chlorination must be carried out through the use of either:
1. Activated charcoal filters. or
2. Sodium bisulfite (Na2HSO3).
 Activated charcoal filter

The use of an activated charcoal filter for de-chlorination of the

potable water is a simple & very effective method.
Activated charcoal absorbs low molecular weight organics, such as
chlorine and chloramine compounds.
However, when manufacturing ultra-pure water the use of
activated charcoal could be problematic. The risk of increased
microbiological fouling and the formation of a biofilm is very
high.
 Dosage of sodium bisulfite

Sodium bisulfite is added to the raw water. Sodium bisulfite

combines with chlorine, which is then separated through reverse
osmosis.
The added quantity must be adjusted.
Removal of carbon dioxide (CO2)

Carbon dioxide represents a problem when generating purified

water via reverse osmosis, as it is not retained by the reverse
osmosis membrane and thus leads to increased conductivity.
Two methods are used to remove carbon dioxide:
Dosage of sodium hydroxide solution: The carbon dioxide is
converted into carbonate, which is retained by reverse osmosis.
Membrane degassing: Through the creation of pressure difference
and are rinsed from the membrane using air.
 Reverse osmosis
Deionization and removal of microorganisms can be carried out in
the reverse osmosis unit.
Reverse osmosis is a physical operation which takes place on
membranes. It reverses the process of osmosis.
A semipermeable membrane retains cations, anions colloidal
systems and bacteria.
The membrane lets through water that is almost pure.

With reverse osmosis, more than 98 % of salts and 90 % of

organic compounds are retained, as well as bacteria and
organisms.
 Reverse osmosis

In order to reverse the process of osmosis, pressure higher than

the osmotic pressure must be applied to the concentrate stream
in order to push water with a low amount of solids through the
membrane.
Reverse osmosis mechanism
Reverse osmosis

Reverse Osmosis

Remove particles, bacteria,

pyrogen, organic, inorganic ions
and silica
Reverse Osmosis
Electro-deionization (EDI, CDI)
Electro-deionization (CDI = Continuous Deionization; EDI =
Electro-deionization.
EDI works by coupling the behavior of ions in the electrical field
with membrane technology.

The anions wander towards the anode.

The cations are transported towards the cathode in the same
manner.
 Advantages of EDI

High purification level (>98%) with small membrane area.

Continuous operation through self-regeneration.
No use of chemicals for regeneration or neutralization.
Retention of high pH values through water division and thus regeneration
Optimum carbon dioxide, silicate and TOC removal
Prevention of multiplication of microorganisms.
Low energy consumption (0.1–1.0 KW/m3) with very low voltage.
Minimum space requirement due to compact design of the module
 Ultra filtration

Ultra filtration (UF) is a separation technology for

separating particles with a size of 0.001 to 0.1 μm.
For ultra pure water production UF hollow fiber
membranes are usually used.
The conductivity of the permeate remains nearly the
same as that of the feed water.
 Ion exchanger

In the ion exchanger (separate bed and mixed bed

system) ions are removed from the water. Ion
exchangers are filled with special resins which are
usually produced from synthetic polymers as balls
(particle size 0.3–1.5 mm.
 Ion-Exchange

• The ion-exchange equipment involves the

passage of water through a column of:
• Cation and Anion exchangers.

Resin is:
• Water-insoluble materials synthetic,
polymerized phenolic, carboxylic, amino, or
sulfonated materials high molecular weight.
 Types of Resins
1. The Cation or acid exchangers.
Which permit the exchange of Cations + Na+, Ca++,
Mg++, etc, (in solution in the tap water) with
hydrogen ion from the resin.
2. The Anion-, or base exchange resins.
Which permit the removal of anions in solution in the
tap water with Cl
The process is as follows:
(M+) indicating the metal or Cation as (Na+)
(X-) indicating the Anion as (Cl-)
Cation Exchange
H-Resin + M+ + X- + H2O → M-Resin + H+ + X-
+ H2O.
Anion Exchange:
Resin-NH2 + H+ + X- + H2O→ Resin-NH2 . HX +
H2O Pure.
● Purified water in this method is named as
demineralized or de-ionized water.
● Used in any pharmaceutical preparation or prescription.
 Purification Plants
• The particular combination of procedures usually depends on the feed
water quality. Usually, the analysis results from the potable water
supplier can be used for initial planning regarding which
combinations will give the desired result.
• There are feed water qualities for which the combination of reverse
osmosis with an EDI is sufficient for the generation of purified
water. For other feed water qualities, softening, reverse osmosis,
CO2-degassing and EDI must be combined to achieve the same
result.
 Distilled Water / Distillers
• It’s an Instrument used to generate distilled water, by boiling the
water and collect the steam in a clean container.
• This water which called Distilled water used mainly in the
preparation of injectable products such as IV. Solutions, Ampoules,
Eye drops, and Liquid Vials.
 Distilled Water / Distillers
• Distilled water is water that has virtually all of its impurities
removed through distillation.
• Distillation involves boiling the water and then condensing the steam
into a clean container, leaving most if not all solid contaminants
behind.
Procedure combination for generation
purified water
System1 System 2 System 3 System 4 System 5 System 6

Activated X
charcoal filter
Softener X X X X

Mixed bed X X
technology
Ultra filtration X X

Reverse X X X X X
osmosis
Degassing X X

EDI/CDI X X X
THANK YOU